arsenic trioxide and atra acute promyelocytic leukaemia (apml)

THE CLATTERBRIDGE CANCER CENTRE NHS FOUNDATION TRUST

Issue Date: 10th July 2020 Review Date: July 2023

of 13 Protocol reference: MPHAATAHA

Author: Aileen McCaughey Authorised by: Drug & Therapeutics Committee Version No: 1.0

Approved for use in:

Arsenic trioxide is recommended, within its marketing authorisation, as an option for inducing

remission and consolidation in acute promyelocytic leukaemia (characterised by the presence

of the t[15;17] translocation or the PML/RAR-alpha gene) in adults with:

untreated, low-to-intermediate risk disease (defined as a white blood cell count of

≤10x109/L), when given with all-trans-retinoic acid (ATRA)

relapsed or refractory disease, after a retinoid and chemotherapy

Blueteq registration required

Dosage - Induction:

Drug Dose Route Frequency

Tretinoin

(All-Trans-

Retinoic-

Acid)

45mg/m2/day (in two equally

divided doses and rounded to

the nearest 10mg capsule)

Oral

Twice daily for 60 days or

until a complete response –

whichever comes first

Arsenic

Trioxide 0.3mg/kg

IV

infusion Days 1-5 (mon-fri)

Arsenic

Trioxide 0.25mg/kg

IV

infusion

Days 9, 12, 16, 19, 23, 26,

30, 33, 37, 40, 44, 47, 51 and

54 (i.e. twice weekly for

seven weeks)

Course length 56 days

Systemic Anti Cancer Therapy Protocol

Arsenic Trioxide and ATRA Acute Promyelocytic Leukaemia (APML)

PROTOCOL REF: MPHAATAHA

(Version No: 1.0)





Dosage – Consolidation (cycles 1-3):


Tretinoin

(All-Trans-

Retinoic-

Acid)




Oral Twice daily days 1-14 and

29-42 of cycle

Arsenic

Trioxide 0.3mg/kg

IV


Arsenic

Trioxide 0.25mg/kg

IV

infusion

Days 9, 12, 16, 19, 23 and 26

(i.e. twice weekly for three

weeks


Dosage – Consolidation (cycle 4):


Tretinoin

(All-Trans-

Retinoic-

Acid)




Oral Twice daily days 1-14

Arsenic

Trioxide 0.3mg/kg

IV


Arsenic

Trioxide 0.25mg/kg

IV

infusion

Days 9, 12, 16, 19, 23 and 26

(i.e. twice weekly for three

weeks


Administration (+/- Counselling Points):

Arsenic trioxide can be given over 4 hours if vasomotor reactions are observed.

It is recommended that tretinoin be administered with a meal or shortly thereafter.

Admission is necessary for induction chemotherapy





Anti-emetic risk (if applicable):

Low emetogenic risk.

Supportive treatments:

Allopurinol 300mg daily for first month. Consider rasburicase if high risk of tumour lysis

syndrome.

Metoclopramide 10mg TDS PRN Antimicrobial prophylaxis as per local policy (avoid drugs that prolong the QTc interval)

Extravasation risk (if applicable):

Arsenic trioxide: non-vesicant

Refer to the network guidance for the prevention and management of extravasation

Interactions:

Tretinoin

Tretinoin is contraindicated with other retinoids (i.e. vitamin A) because of the risk of

symptoms suggestive of hypervitaminosis A for daily doses greater than 10,000 IU.

Tretinoin is also contraindicated with tetracyclines: risk of intracranial hypertension

(pseudotumor cerebri).

As tretinoin is metabolised by the hepatic P450 system, there is the potential for alteration of

pharmacokinetics parameters in patients administered concomitant medications that are also

inducers or inhibitors of this system. Medications that generally induce hepatic P450 enzymes

include rifampicin, glucocorticoids, phenobarbital and pentobarbital. Medications that

generally inhibit hepatic P450 enzymes include ketoconazole, cimetidine, erythromycin,

verapamil, diltiazem and ciclosporin. There are no data to suggest that co-use with these

medications increases or decreases either efficacy or toxicity of tretinoin.

Cases of fatal thrombotic complications have been reported rarely in patients concomitantly

treated with tretinoin and antifibrinolytic agents such as tranexamic acid, aminocaproic acid





and aprotinin. Therefore, caution should be exercised when administering tretinoin

concomitantly with these agents.

Arsenic trioxide

No formal assessments of pharmacokinetic interactions between arsenic trioxide and other

therapeutic medicinal products have been conducted.

QT/QTc prolongation is expected during treatment with arsenic trioxide, and torsade de

pointes and complete heart block have been reported. Patients who are receiving, or who

have received, medicinal products known to cause hypokalaemia or hypomagnesaemia, such

as diuretics or amphotericin B, may be at higher risk for torsade de pointes. Caution is

advised when arsenic trioxide is co-administered with other medicinal products known to

cause QT/QTc interval prolongation such as macrolide antibiotics, the antipsychotic

thioridazine, or medicinal products known to cause hypokalaemia or hypomagnesaemia.

Hepatotoxic effects may occur during the treatment with arsenic trioxide, caution is advised

when arsenic is co-administered with other medicinal products known to cause hepatotoxic

effects.

Treatment schedule: Induction

Day Drug Dose Route Diluent and rate

1 to 60

Tretinoin




PO With food. Stop once patient is in complete remission

1 Arsenic trioxide 0.3mg/kg IV infusion

Over 2 hours in 250mls NaCl 0.9%*









9 Arsenic trioxide 0.25mg/m2 IV Over 2 hours in 250mls NaCl 0.9%*





infusion

12 Arsenic trioxide 0.25mg/m2 IV infusion


























Treatment schedule: Consolidation cycles 1-3


1 to 14 and 29-42

Tretinoin

45mg/m2/day (in two equally divided doses and rounded to the nearest 10mg capsule)

PO With food.

1 Arsenic trioxide 0.3mg/kg

IV infusion



IV infusion



IV infusion



IV infusion


5 Arsenic trioxide 0.3mg/kg IV Over 2 hours in 250mls NaCl 0.9%*





infusion


IV infusion



IV infusion



IV infusion



IV infusion



IV infusion



IV infusion


Treatment schedule: Consolidation cycle 4


1 to 14

Tretinoin

45mg/m2/day (in two equally divided doses and rounded to the nearest 10mg capsule)

PO With food.


IV infusion



IV infusion



IV infusion



IV infusion



IV infusion



IV infusion



IV infusion



IV infusion



IV infusion



IV infusion



IV infusion






* NB. Arsenic Trioxide infusion duration may be extended up to 4 hours if vasomotor

reactions, e.g. flushing, tachycardia and dizziness, are observe. If patients suffer

severe symptoms or hypotension then the infusion should be stopped until recovery

and then recommenced at a reduced rate.

Main toxicities:

Thrombocytopenia, neutropenia, anaemia, nausea, vomiting, diarrhoea Differentiation or ATRA syndrome This potentially life-threatening complication of ATRA therapy is characterized by fluid

retention and features of capillary leak and is most likely related to surface adhesion molecule

modulation and cytokine release following induction of differentiation of APL cells. Symptoms

and signs include cough, dyspnoea, fever, weight gain, oedema, pleural and pericardial

effusions and pulmonary infiltrates differentiation syndrome occurs in up to a third of patients

receiving ATRA as single-agent induction therapy and was fatal in approximately 30% in early

studies. The syndrome typically develops approximately 10 days after initiation of ATRA, but

can appear as early as 2 days and is commonly, but not invariably, associated with a rising

peripheral WBC count.

Patients on ATRA should be observed very carefully for symptoms, signs or falling oxygen

saturation levels indicative of impending differentiation syndrome. If there are clinical

suspicions of this complication;

ATRA should be temporarily discontinued and steroids administered promptly

(dexamethasone 10 mg IV BD until disappearance of symptoms and signs, and for a

minimum of 3 d), which may prevent progression to the full blown syndrome.

ATRA can then be cautiously re-introduced.

Evidence to date suggests that steroids act by modulating the surface adhesion

characteristics of APL blasts, preventing ATRA-induced aggregation that accompanies

differentiation. Its occurrence during induction is not a contraindication to use of ATRA later in

the patient's treatment course (including management of any relapse). Patients with a

relatively high presenting WBC (>10 × 109/l) have in some studies been reported to be at

higher risk of differentiation syndrome during induction and some trial groups advocate use of

prophylactic steroids as a component of induction therapy.





Hepatotoxicity

Arsenic and tretinoin have been associated with hepatotoxicity – see below for details. NB

toxic effects can be resolved with temporary discontinuation of tretinoin and/or arsenic.

Pseudotumour Cerebri

The presence of severe headaches with nausea, vomiting, and visual disorders, generally

developing in patients aged < 20 years. It is often necessary to discontinue ATRA temporarily

and to administer opiates.

Lipids

Up to 60% experience reversible hypercholesterolemia and/or hypertriglyceridemia. Venous

thrombosis and myocardial infarction have been reported in patients ordinarily at low risk for

such complications.

QT prolongation

Arsenic has been associated with QTc interval prolongation with associated heart block and

fatal ventricular arrhythmias. Prior to initiating therapy with arsenic, a 12-lead ECG must be

performed and serum electrolytes (potassium, calcium, and magnesium) and creatinine must

be assessed; pre-existing electrolyte abnormalities must be corrected and, if possible,

medicinal products that are known to prolong the QT interval must be discontinued. Patients

with risk factors of QTc prolongation or risk factors of torsade de pointes should be monitored

with continuous cardiac monitoring (ECG). For QTc greater than 500 msec, corrective

measures must be completed and the QTc reassessed with serial ECGs and, if available, a

specialist advice could be sought prior to considering using arsenic. During therapy with

arsenic, potassium concentrations must be kept above 4 mmol/l and magnesium

concentrations must be kept above 0.74mmol/l. Patients who reach an absolute QT interval

value > 500 msec must be reassessed and immediate action must be taken to correct

concomitant risk factors, if any, while the risk/benefit of continuing versus suspending arsenic

therapy must be considered. If syncope, rapid or irregular heartbeat develops, the patient

must be hospitalised and monitored continuously, serum electrolytes must be assessed,

arsenic therapy must be temporarily discontinued until the QTc interval regresses to below

460 msec, electrolyte abnormalities are corrected, and the syncope and irregular heartbeat

cease. After recovery, treatment should be resumed at 50 % of the preceding daily dose. If





QTc prolongation does not recur within 7 days of restarting treatment at the reduced dose,

treatment with arsenic can be resumed at 0.11 mg/kg body weight per day for a second week.

The daily dose can be escalated back to 100 % of the original dose if no prolongation occurs.

There are no data on the effect of arsenic trioxide on the QTc interval during the infusion.

Electrocardiograms must be obtained at least twice weekly, and more frequently for clinically

unstable patients, during induction and consolidation.

Coagulopathy

A major cause of treatment failure is induction death as a result of haemorrhage, which

reflects to varying degree DIC excessive fibrinolysis and proteolysis. Patients with higher

presenting WBC (i.e. >10 × 109/l) are at highest risk of haemorrhagic death. Patients with

very high presenting leucocyte counts should not undergo leucopheresis, which commonly

precipitates fatal exacerbation of the coagulopathy.

High rates of induction death have also been observed when low-dose chemotherapy was

used to attempt to reduce WBC in the first instance (Vahdat et al, 1994). Haemorrhagic

deaths may be reduced by rigorous monitoring of the coagulation profile and administration of

appropriate replacement therapy until morphological CR has been attained.

APTT, prothrombin time, thrombin time, fibrinogen level and platelet count should be checked

at least twice daily during the early stages of treatment. Coagulation times should be kept

within the normal range using FFP or Riaspin as replacement. Fibrinogen levels may be low

due to DIC and cryoprecipitate should be given as replacement aiming for a level of

approximately 2 g/l. Elevated levels of fibrinogen should be avoided because of the increased

risk of thrombosis associated with APL, which may be further exacerbated by ATRA.

The platelet count should ideally be maintained above 50 × 109/l until morphological

remission has been confirmed. Clinical studies have not established proven benefit for use of

heparin or anti-fibrinolytic agents as a means of decreasing induction death rates in APL and

their routine use is not recommended. Indeed, anti-fibrinolytic agents when combined with

ATRA could potentially increase the inherent risk of thrombotic complications. Nevertheless,

anti-fibrinolytic agents could be contemplated in situations of life-threatening haemorrhage in

the presence of normal coagulation assays.





Investigations and treatment plan: Induction

Pre D1 D2 D3 D4 D5 D9 D12 D16 D19 D23 D26 D30 D33 D37 D40 D44 D47 D51 D54 Ongoing

Informed consent x

Clinical Assessment x x x x x x x x x x

SACT Assessment (including performance status and toxicity assessment)

x x x x x x x x x x x x x x x x x x x

Hepatitis B core antibody and surface antigens & Hep C & HIV 1+2, CMV, VZV

x

PML-RARA screen x

Clotting screen + fibrinogen x x x x x x x x x x x x x x x x x x x x

Daily until haematological

remission

FBC x x x x x x x x x x x x x x x x x x x x

Glucose x x x x x x x x x x x x x x x x X

U&E & LFTs & Magnesium x x x x x x x x x x x x x x x x x

CrCl (Cockcroft and Gault) x

Bone Marrow Biopsy x

Repeat once haematological

remission achieved

ECHO x

ECG x x x x x x x x x x x x x x x x x More often in

unstable patients





Investigations and treatment plan: Consolidation

Weight x x x x x x x x x x x x x x x x x x

Height x

Pre D1 D2 D3 D4 D5 D9 D12 D16 D19 D23 D26 D30 D33 D37 D40 D44 D47 D51 D54 Ongoing

Clinical Assessment x x x x x x x x

Senior medical review before cycle starts

thereafter CNS once weekly

SACT Assessment (including performance status and toxicity assessment)

x x x x x x x x x x x Every cycle

Clotting screen + Fibrinogen x

FBC x x x x x x x x x x x x

Glucose x x x x x x x x x

U&E & LFTs & Magnesium x x x x x x x x x x x x

CrCl (Cockcroft and Gault) x

Bone Marrow Biopsy

Between days 44-54

ECG x x x x x x x x

Weight x





Dose Modifications and Toxicity Management:

Haematological toxicity:

Induction should start regardless of cytopenias.

For subsequent cycles proceed if-

ANC ≥ 1.5 x 109/L Plt ≥ 100 x 109/L

These haematological guidelines assume that patients are well with good performance

status, that other acute toxicities have resolved and the patient has not had a previous

episode of neutropenic sepsis.

Dosing in renal and hepatic impairment:

Tretinoin

CrCl (ml/min) Dose of tretinoin

<50ml/min 25mg/m2 daily

Liver Dysfunction

Hepatic insufficiency 25mg/m2 daily

Arsenic

CrCl (ml/min) Dose of arsenic

<30ml/min Consider 50% dose reduction

Liver dysfunction - prior to treatment

Hepatotoxicity is a known side effect of arsenic therefore caution is required if arsenic is

started in anyone with known hepatic impairment.

Liver Dysfunction Dose of arsenic

Childs Pugh C Consider 50% dose reduction

Arrhythmias:

If syncope, rapid or irregular heartbeat develops, the patient must be hospitalised and

monitored continuously, serum electrolytes must be assessed, arsenic therapy must be

temporarily discontinued until the QTc interval regresses to below 460 msec, electrolyte

abnormalities are corrected, and the syncope and irregular heartbeat cease. After





recovery, treatment should be resumed at 50 % of the preceding daily dose. If QTc

prolongation does not recur within 7 days of restarting treatment at the reduced dose,

treatment with arsenic can be resumed at 0.11 mg/kg body weight per day for a second

week. The daily dose can be escalated back to 100 % of the original dose if no

prolongation occurs.

References:

1. Summary of Product Characteristics for Arsenic (Teva Pharma B.V.), viewed

January 2020 (available at https://www.medicines.org.uk/emc

2. Summary of Product Characteristics for Tretinoin (Cheplapharm Arzneimittel

GmbH), viewed January 2020 (available at https://www.medicines.org.uk/emc)

3. Krens S D, Lassche, Jansman G F G A, et al. Dose recommendations for

anticancer drugs in patients with renal or hepatic impairment. Lancet Oncol 2019;

20: e201–08.

4. Thames Valley Strategic Clinical Network. ATRA and Arsenic Protocol. October

2019.

https://www.medicines.org.uk/emc

https://www.medicines.org.uk/emc

arsenic trioxide and atra acute promyelocytic leukaemia (apml)

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